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BackgroundDepression during pregnancy and after the birth of a child is highly prevalent and an important public health problem. Psychological interventions are the first-line treatment and, although a considerable number of randomized trials have been conducted, no recent comprehensive meta-analysis has evaluated treatment effects.MethodsWe used an existing database of randomized controlled trials of psychotherapies for adult depression and included studies aimed at perinatal depression. Random effects models were used in all analyses. We examined the effects of the interventions in the short and long term, and also examined secondary outcomes.ResultsForty-three studies with 49 comparisons and 6270 participants between an intervention and control group were included. The overall effect size was g = 0.67 [95% confidence interval (CI) 0.45~0.89; numbers needed-to-be-treated = 4.39] with high heterogeneity (I2 = 80%; 95% CI 75~85). This effect size remained largely unchanged and significant in a series of sensitivity analyses, although some publication bias was found. The effects remained significant at 6–12 months follow-up. Significant effects were also found for social support, anxiety, functional limitations, parental stress and marital stress, although the number of studies for each outcome was low. All results should be considered with caution because of the high levels of heterogeneity in most analyses.ConclusionsPsychological interventions are probably effective in the treatment of perinatal depression, with effects that last at least up to 6–12 months and probably also have effects on social support, anxiety, functional impairment, parental stress, and marital stress.

Background Cluster-C personality disorders (PDs) are highly prevalent in clinical practice and are associated with unfavourable outcome and chronicity of all common mental health disorders (e.g. depression and anxiety disorders). Although several forms of individual psychotherapy are commonly offered in clinical practice for this population, evidence for differential effectiveness of different forms of psychotherapy is lacking. Also, very little is known about the underlying working mechanisms of these psychotherapies. Finding evidence on the differential (cost)-effectiveness for this group of patients and the working mechanisms of change is important to improve the quality of care for this vulnerable group of patients. Objective In this study, we will compare the differential (cost)-effectiveness of three individual psychotherapies: short-term psychodynamic supportive psychotherapy (SPSP), affect phobia therapy (APT) and schema therapy (ST). Although these psychotherapies are commonly used in clinical practice, evidence for the Cluster-C PDs is limited. Additionally, we will investigate predictive factors, non-specific and therapy-specific mediators. Methods This is a mono-centre randomized clinical trial with three parallel groups: (1) SPSP, (2) APT, (3) ST. Randomization on patient level will be pre-stratified according to type of PD. The total study population to be included consists of 264 patients with Cluster-C PDs or other specified PD with mainly Cluster-C traits, aged 18–65 years, seeking treatment at NPI, a Dutch mental health care institute specialized in PDs. SPSP, APT and ST (50 sessions per treatment) are offered twice a week in sessions of 50 min for the first 4 to 5 months. After that, session frequency decreases to once a week. All treatments have a maximum duration of 1 year. Change in the severity of the PD (ADP-IV) will be the primary outcome measure. Secondary outcome measures are personality functioning, psychiatric symptoms and quality of life. Several potential mediators, predictors and moderators of outcome are also assessed. The effectiveness study is complemented with a cost-effectiveness/utility study, using both clinical effects and quality-adjusted life-years, and primarily based on a societal approach. Assessments will take place at baseline, start of treatment and at 1, 3, 6, 9, 12, 18, 24 and 36 months. Discussion This is the first study comparing psychodynamic treatment to schema therapy for Cluster-C PDs. The naturalistic design enhances the clinical validity of the outcome. A limitation is the lack of a control group for ethical reasons. Trial registration NL72823.029.20 [Registry ID: CCMO]. Registered on 31 August 2020. First participant included on 23 October 2020.

Background: Insomnia is the transdiagnostically shared most common complaint in disorders of anxiety, stress and emotion regulation. Current cognitive behavioral therapies (CBT) for these disorders do not address sleep, while good sleep is essential for regulating emotions and learning new cognitions and behaviours: the core fundaments of CBT. This transdiagnostic randomized control trial (RCT) evaluates whether guided internet-delivered cognitive behavioral therapy for insomnia (iCBT-I) (1) improves sleep, (2) affects the progression of emotional distress and (3) enhances the effectiveness of regular treatment of people with clinically relevant symptoms of emotional disorders across all mental health care (MHC) echelons. Methods: We aim for 576 completers with clinically relevant symptoms of insomnia as well as at least one of the dimensions of generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder (PD), posttraumatic stress disorder (PTSD) or borderline personality disorder (BPD). Participants are either pre-clinical, unattended, or referred to general- or specialized MHC. Using covariate-adaptive randomization, participants will be assigned to a 5 to 8-week iCBT-I (i-Sleep) or a control condition (sleep diary only) and assessed at baseline, and after two and eight months. The primary outcome is insomnia severity. Secondary outcomes address sleep, severity of mental health symptoms, daytime functioning, mental health protective lifestyles, well-being, and process evaluation measures. Analyses use linear mixed-effect regression models. Discussion: This study can reveal for whom, and at which stage of disease progression, better nights could mean substantially better days. Trial registration: International Clinical Trial Registry Platform (NL9776). Registered on 2021-10-07.

QUESTION: Can existing post-treatment prognostic models for predicting neck pain recovery (primarily in terms of disability and secondarily in terms of pain intensity and perceived improvement) be externally validated and updated at the end of the treatment period and at 6 and 12 weeks of follow-up in a new Dutch cohort of people with neck pain treated with guideline-based usual care physiotherapy?DESIGN: External validation and model updating in a new prospective cohort of three previously developed prognostic models.PARTICIPANTS: People with (sub)acute neck pain and registered for primary care physiotherapy treatment.OUTCOME MEASURES: Recovery of disability, pain intensity, and perceived recovery at 6 and 12 weeks and at the end of the treatment period.RESULTS: Discriminative performance (c-statistic) of the disability model at 6 weeks was 0.73 (95% CI 0.69 to 0.77) and reasonably well calibrated after intercept recalibration. The disability model at 12 weeks and at the end of the treatment period showed discriminative c-statistic performance values of 0.69 (95% CI 0.64 to 0.73) and 0.68 (95% CI 0.63 to 0.72), respectively, and was well calibrated. Pain models and perceived recovery models did not reach acceptable performance. Cervical mobility added value to the disability models and pain catastrophising to the disability and pain models at 6 weeks.DISCUSSION: Broad external validation of the disability model was successful in people with (sub)acute neck pain and clinicians may use this model in clinical practice with reasonable accuracy. Further research is required to assess the disability model's clinical impact and generalisability, and to identify additional valuable model predictors.REGISTRATION: https://osf.io/a6r3k/.

BACKGROUND: Platelet RNA sequencing has been shown to accurately detect cancer in previous studies. OBJECTIVES: To compare the diagnostic accuracy of platelet RNA sequencing with standard-of-care limited cancer screening in patients with unprovoked venous thromboembolism (VTE). METHODS: Patients aged ≥40 years with unprovoked VTE were recruited at 13 centers and followed for 12 months for cancer. Participants underwent standard-of-care limited cancer screening, and platelet RNA sequencing analysis was performed centrally at study end for cases and selected controls. Sensitivity and specificity were calculated, using the predefined primary positivity threshold of 0.54 for platelet RNA sequencing aiming at 86% test sensitivity, and an additional predefined threshold of 0.89 aiming at 99% test specificity. RESULTS: A total of 476 participants were enrolled, of whom 25 (5.3%) were diagnosed with cancer during 12-month follow-up. For each cancer patient, 3 cancer-free patients were randomly selected for the analysis. The sensitivity of limited screening was 72% (95% CI, 52-86) at a specificity of 91% (95% CI, 82-95). The area under the receiver operator characteristic for platelet RNA sequencing was 0.54 (95% CI, 0.41-0.66). At the primary positivity threshold, all patients had a positive test, for a sensitivity estimated at 100% (95% CI, 87-99) and a specificity of 8% (95% CI, 3.7-16.4). At the secondary threshold, sensitivity was 68% (95% CI, 48-83; p value compared with limited screening 0.71) at a specificity of 36% (95% CI, 26-47). CONCLUSION: Platelet RNA sequencing had poor diagnostic accuracy for detecting occult cancer in patients with unprovoked VTE with the current algorithm. ispartof: J Thromb Haemost vol:21 issue:4 pages:905-916 ispartof: location:England status: published

ObjectiveConvert the Medical Information Mart for Intensive Care (MIMIC)-IV database into Health Level 7 Fast Healthcare Interoperability Resources (FHIR). Additionally, generate and publish an openly available demo of the resources, and create a FHIR Implementation Guide to support and clarify the usage of MIMIC-IV on FHIR.Materials and MethodsFHIR profiles and terminology system of MIMIC-IV were modeled from the base FHIR R4 resources. Data and terminology were reorganized from the relational structure into FHIR according to the profiles. Resources generated were validated for conformance with the FHIR profiles. Finally, FHIR resources were published as newline delimited JSON files and the profiles were packaged into an implementation guide.ResultsThe modeling of MIMIC-IV in FHIR resulted in 25 profiles, 2 extensions, 35 ValueSets, and 34 CodeSystems. An implementation guide encompassing the FHIR modeling can be accessed at mimic.mit.edu/fhir/mimic. The generated demo dataset contained 100 patients and over 915 000 resources. The full dataset contained 315 000 patients covering approximately 5 840 000 resources. The final datasets in NDJSON format are accessible on PhysioNet.DiscussionOur work highlights the challenges and benefits of generating a real-world FHIR store. The challenges arise from terminology mapping and profiling modeling decisions. The benefits come from the extensively validated openly accessible data created as a result of the modeling work.ConclusionThe newly created MIMIC-IV on FHIR provides one of the first accessible deidentified critical care FHIR datasets. The extensive real-world data found in MIMIC-IV on FHIR will be invaluable for research and the development of healthcare applications.

Objective: Electroconvulsive therapy (ECT) is the most effective treatment for patients with severe major depressive disorder (MDD). Given the known sex differences in MDD, improved knowledge may provide more sex-specific recommendations in clinical guidelines and improve outcome. In the present study we examine sex differences in ECT outcome and its predictors. Methods: Clinical data from 20 independent sites participating in the Global ECT-MRI Research Collaboration (GEMRIC) were obtained for analysis, totaling 500 patients with MDD (58.6 % women) with a mean age of 54.8 years. Severity of depression before and after ECT was assessed with validated depression scales. Remission was defined as a HAM-D score of 7 points or below after ECT. Variables associated with remission were selected based on literature (i.e. depression severity at baseline, age, duration of index episode, and presence of psychotic symptoms). Results: Remission rates of ECT were independent of sex, 48.0 % in women and 45.7 % in men (X2(1) = 0.2, p = 0.70). In the logistic regression analyses, a shorter index duration was identified as a sex-specific predictor for ECT outcome in women (X2(1) = 7.05, p = 0.01). The corresponding predictive margins did show overlapping confidence intervals for men and women. Conclusion: The evidence provided by our study suggests that ECT as a biological treatment for MDD is equally effective in women and men. A shorter duration of index episode was an additional sex- specific predictor for remission in women. Future research should establish whether the confidence intervals for the corresponding predictive margins are overlapping, as we find, or not.

Srijana Adhikari,1 Ruth Marie Antoinette van Nispen,2 Ellen Bernadette Maria Elsman,2 Fleur van Rens,3 Ger van Rens2 1Department of Pediatric Ophthalmology and Strabismus, Tilganga Institute of Ophthalmology, Kathmandu, Nepal; 2Department of Ophthalmology, VU University Medical Centre and the Amsterdam Public Health Research Institute, Amsterdam, the Netherlands; 3Discipline of Exercise Science, Murdoch University, Murdoch, WA, AustraliaCorrespondence: Srijana Adhikari, Tilganga Institute of Ophthalmology, Gaushala, PO Box 561, Kathmandu, Nepal, Tel +977-9849287387, Email srij_a@yahoo.comPurpose: To study the causes of moderate and severe visual impairment (VI) and blindness and its changing trends in Nepalese children.Patients and Methods: A cross-sectional descriptive study was conducted. Participants, aged 7 to 17 years were recruited from integrated schools for the blind and the outpatient department of a tertiary eye hospital in Kathmandu. VI and blindness were categorized according to World Health Organization (WHO) categories and its protocol for eye examination of children with blindness and VI was followed. Findings were compared to former studies from Nepal.Results: A total of 200 children were included, of whom 45% had moderate VI, 5% had severe VI, and 50% were blind. Mean age of children with VI and blindness was 11.1 (SD = 3.3) and 12.9 (SD = 3) years, respectively. Forty percent of children with VI and 38% of blind children were female. In our study, retina (39%) and whole globe (32%) were the most common anatomical site of involvement in children with VI and blindness, respectively, while cornea was the most common anatomical site of involvement in former studies. Heredity (43%) was the most common etiological factor although in 24.5% of all children, etiology was unknown. In 43.5% of children, blindness and VI was due to avoidable causes.Conclusion: In relatively many children, the etiology of VI and blindness could be either prevented or treated. Compared to former studies from Nepal, there is a changing trend in the etiology of severe VI and blindness.Keywords: childhood blindness, Nepal, visual impairment, pediatric

Telemonitoring disease activity with electronic patient-reported outcomes (ePROs) may reduce the workload of rheumatic care by decreasing outpatient clinic visits. However, low adherence to reporting ePROs is frequently observed. Our objective was to identify facilitators and barriers to weekly monitoring of disease activity with ePROs. Patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) who recently participated in one of the two telemonitoring studies with ePROs completed in a smartphone app, were invited to participate in focus group discussions (FGD). Thematic analysis was used to identify themes that play a role in the decision to continue or stop reporting weekly ePROs. A total of 22 patients participated in three FGDs. Five themes were identified that were of importance to adhere to telemonitoring: (1) questionnaire frequency, (2) discussing results of completed ePROs, (3) physical consultations, (4) patient insight into disease activity and (5) user experience of the app. All themes contained both barrier and facilitator elements. The results suggest that to improve adherence to telemonitoring of disease activity with ePROs, the perceived benefits of completing ePROs should be maximized. This can be done by providing patients the ability to skip (unneeded) physical consultations in case of low disease activity, and training clinicians to always discuss the completed ePROs. In addition, it is essential to reduce the effort to report ePROs, by tailoring the frequency of ePROs based on the patients’ disease activity or preference, aiming for optimal app functionality as well as by sending notifications when new ePROs are available.

Objective:Birth weight, fetal growth and placental function influence cognitive development. The gradient of these associations is understudied, especially among those with a birth weight considered appropriate-for-gestational age. The aim of this study was to evaluate the associations between birth-weight centile and intellectual development in term/near-term infants across the entire birth-weight spectrum, in order to provide a basis for better understanding of the long-term implications of fetal growth restriction and reduced placental function.Methods:This was a population-based cohort study of 266 440 liveborn singletons from uncomplicated pregnancies, delivered between 36 and 42 weeks of gestation. Perinatal data were obtained from the Dutch Perinatal Registry over the period 2003–2008 and educational data for children aged approximately 12 years were obtained from Statistics Netherlands over the period 2016–2019. Regression analyses were conducted to assess the association of birth-weight centile with school performance. The primary outcomes were mean school performance score, on a scale of 501–550, and proportion of children who reached higher secondary school level.Results:Mean school performance score increased gradually with increasing birth-weight centile, from 533.6 in the 1st–5th birth-weight-centile group to 536.8 in the 81st–85th birth-weight-centile group. Likewise, the proportion of children at higher secondary school level increased with birth-weight centile, from 43% to 57%. Compared with the 81st–85th birth-weight-centile group, mean school performance score and proportion of children at higher secondary school level were significantly lower in all birth-weight-centile groups below the 80th centile, after adjusting for confounding factors.Conclusions:Birth-weight centile is associated positively with school performance at 12 years of age across the entire birth-weight spectrum, well beyond the conventional and arbitrary cut-offs for suspected fetal growth restriction. This underlines the importance of developing better tools to diagnose fetal growth restriction and reduced placental function, and to identify those at risk for associated short- and long-term consequences. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Introduction: Since the eight edition of the Union for In-ternational Cancer Control and American Joint Committee on Cancer TNM classification system, the primary tumor pT stage is determined on the basis of presence and size of the invasive components. The aim of this study was to identify histologic features in tumors with lepidic growth pattern which may be used to establish criteria for distinguishing invasive from noninvasive areas.Methods: A Delphi approach was used with two rounds of blinded anonymized analysis of resected nonmucinous lung adenocarcinoma cases with presumed invasive and nonin-vasive components, followed by one round of reviewer de-anonymized and unblinded review of cases with known outcomes. A digital pathology platform was used for measuring total tumor size and invasive tumor size. Results: The mean coefficient of variation for measuring total tumor size and tumor invasive size was 6.9% (range: 1.7%-22.3%) and 54% (range: 14.7%-155%), respectively, with substantial variations in interpretation of the size and location of invasion among pathologists. Following the presentation of the results and further discussion among members at large of the International Association for the Study of Lung Cancer Pathology Committee, extensive epithelial proliferation (EEP) in areas of collapsed lepidic growth pattern is recognized as a feature likely to be associated with invasive growth. The EEP is characterized by multilayered luminal epithelial cell growth, usually with high-grade cytologic features in several alveolar spaces.Conclusions: Collapsed alveoli and transition zones with EEP were identified by the Delphi process as morphologic features that were a source of interobserver variability. Definition criteria for collapse and EEP are proposed to improve reproducibility of invasion measurement.(c) 2022 International Association for the Study of Lung Cancer.

Ellen Ricke,1 Eric W Bakker2 1Department of Social Psychology, University of Groningen, Groningen, the Netherlands; 2Department of Epidemiology and Data Science | Division EBM, Academic Medical Centre, Amsterdam, the NetherlandsCorrespondence: Ellen Ricke, Department of Social Psychology, University of Groningen, Grote Kruisstraat 2/1, Groningen, 9712 TS, the Netherlands, Tel +31 6 211 817 02, Email E.Ricke@rug.nlPurpose: Pulmonary rehabilitation (PR) is considered a cost-effective method of improving health-related quality of life in patients with chronic obstructive pulmonary disease (COPD). However, increasing demand and increasing costs of supply demands for sustainable and affordable care. One of the possible solutions to keep care affordable is self-management. A challenge here is non-adherence. Understanding who are adherent and who are non-adherent could be helpful to differentiate between patients who need more or less support. Therefore, the aim of this study was to develop and validate a model to predict adherence to PR in patients with COPD.Patients and methods: A multivariable logistic regression model for exercise adherence was developed. Eight candidate predictors, that were prespecified, were obtained in a prospective cohort study from 196 patients with COPD following PR in 53 primary physiotherapy practices in the Netherlands and Belgium, between January 2021 and August 2022. To create a parsimonious model, variable selection using backward selection was performed with a p-value of > 0.05 for elimination. Model performance was assessed by discrimination, calibration and clinical utility. Internal validation was assessed by bootstrapping (n = 500).Results: The final model included four predictors: intention, depression, MRC-score and alliance. The optimism-corrected AUC after bootstrap internal validation was 0.79 (95% CI, 0.72– 0.85). Calibration plots suggested good calibration and decision curve analysis showed great net benefit in a wide range of risk thresholds.Conclusion: The exercise adherence prediction model has potential for clinical utility to predict adherence in patients with COPD. Information from such a model can be used to manage the patient instead of managing the disease, and thereby to determine the treatment frequency for each individual patient. As a result, healthcare capacity might be better distributed, potentially reducing pressure on healthcare without compromising the effectiveness of PR for the individual patient.Keywords: chronic obstructive pulmonary disease, sustainable healthcare, pulmonary rehabilitation, self-management

Background: Ethnic minority groups experience a disproportionately high burden of infections, hospitalizations and mortality due to COVID-19, and therefore should be especially encouraged to receive SARS-CoV-2 vaccination. This study aimed to investigate the intent to vaccinate against SARS-CoV-2, along with its determinants, in six ethnic groups residing in Amsterdam, the Netherlands. Methods: We analyzed data of participants enrolled in the population-based multi-ethnic HELIUS cohort, aged 24 to 79 years, who were tested for SARS-CoV-2 antibodies and answered questions on vaccination intent from November 23, 2020 to March 31, 2021. During the study period, SARS-CoV-2 vaccination in the Netherlands became available to individuals working in healthcare or > 75 years old. Vaccination intent was measured by two statements on a 7-point Likert scale and categorized into low, medium, and high. Using ordinal logistic regression, we examined the association between ethnicity and lower vaccination intent. We also assessed determinants of lower vaccination intent per ethnic group. Results: A total of 2,068 participants were included (median age 56 years, interquartile range 46–63). High intent to vaccinate was most common in the Dutch ethnic origin group (369/466, 79.2%), followed by the Ghanaian (111/213, 52.1%), South-Asian Surinamese (186/391, 47.6%), Turkish (153/325, 47.1%), African Surinamese (156/362, 43.1%), and Moroccan ethnic groups (92/311, 29.6%). Lower intent to vaccinate was more common in all groups other than the Dutch group (P < 0.001). Being female, believing that COVID-19 is exaggerated in the media, and being < 45 years of age were common determinants of lower SARS-CoV-2 vaccination intent across most ethnic groups. Other identified determinants were specific to certain ethnic groups. Conclusions: Lower intent to vaccinate against SARS-CoV-2 in the largest ethnic minority groups of Amsterdam is a major public health concern. The ethnic-specific and general determinants of lower vaccination intent observed in this study could help shape vaccination interventions and campaigns.

Prior models have been developed to predict survival for patients with esophagogastric cancer undergoing curative treatment or first-line chemotherapy (SOURCE models). Comprehensive clinical prediction models for patients with esophagogastric cancer who will receive second-line chemotherapy or best supportive care are currently lacking. The aim of our study was to develop and internally validate a new clinical prediction model, called SOURCE beyond first-line, for survival of patients with metastatic esophagogastric adenocarcinoma after failure of first-line palliative systemic therapy. Patients with unresectable or metastatic esophageal or gastric adenocarcinoma (2015-2017) who received first-line systemic therapy (N = 1067) were selected from the Netherlands Cancer Registry. Patient, tumor and treatment characteristics at primary diagnosis and at progression of disease were used to develop the model. A Cox proportional hazards regression model was developed through forward and backward selection using Akaike's Information Criterion. The model was internally validated through 10-fold cross-validations to assess performance. Model discrimination (C-index) and calibration (slope and intercept) were used to evaluate performance of the complete and cross-validated models. The final model consisted of 11 patient tumor and treatment characteristics. The C-index was 0.75 (0.73-0.78), calibration slope 1.01 (1.00-1.01) and calibration intercept 0.01 (0.01-0.02). Internal cross-validation of the model showed that the model performed adequately on unseen data: C-index was 0.79 (0.77-0.82), calibration slope 0.93 (0.85-1.01) and calibration intercept 0.02 (-0.01 to 0.06). The SOURCE beyond first-line model predicted survival with fair discriminatory ability and good calibration.

STUDY OBJECTIVES: We investigated the prevalence of self-reported insomnia symptoms in people with type 2 diabetes and assessed the association with metabolic outcomes and the mediating role of lifestyle factors. METHODS: In a prospective cohort of 1,272 participants with type 2 diabetes (63.4% male, age 68.7 ± 9 years) we measured insomnia symptoms using the Insomnia Severity Index and metabolic outcomes as hemoglobin A1c, glucose, lipids, and body mass index at baseline and at 1 year follow-up. Linear regression analyses assessed the association between insomnia symptoms and metabolic outcomes, corrected for demographic factors, comorbidities, and body mass index. Mediation analyses were conducted for lifestyle factors. RESULTS: The prevalence of mild and severe insomnia symptoms was 23.0% and 10.7%, respectively. When adjusted for demographic factors and comorbidities, cross-sectionally severe insomnia symptoms were associated with higher body mass index (β = 0.97 kg/m2; 95% confidence interval 0.04: 1.89) compared to no insomnia symptoms. Cross-sectionally, no associations were observed for the other metabolic outcomes. Additionally, no prospective associations were observed with any of the outcomes. Finally, physical activity mediated the association between severe insomnia symptoms and body mass index by 29.3%. CONCLUSIONS: About a third of people with type 2 diabetes experience self-reported insomnia symptoms, but insomnia symptoms were not associated with metabolic outcomes in people with type 2 diabetes. CITATION: Groeneveld L, den Braver NR, Beulens JWJ, et al. The prevalence of self-reported insomnia symptoms and association with metabolic outcomes in people with type 2 diabetes: the Hoorn Diabetes Care System cohort. J Clin Sleep Med. 2023;19(3):539-548.

Research on the relational effects of stigma must move beyond the intergroup context and, most importantly, focus upon the ways in which stigma itself shapes social relationships. In order to more deeply investigate the relational consequences of social stigma, researchers interested in this topic need to consider the potential contributions of relationship science. Drawing upon past theory, we pose four overarching questions that may help bridge research on social stigma with relationship science: (1) What types of relationships are relevant to understanding the social consequences of stigma? (2) How do relationships operate when partners are faced with social stigma? (3) What psychosocial tendencies do people whose identities are stigmatized bring to their relationships? (4) How does the broader social context affect relationships for members of stigmatized groups? We also consider methodological advances from relationship science, broadly defined, that may progress research in this area. Finally, we highlight the importance of eliminating discriminatory policy as well as introducing policy aimed at remediating social inequalities to ensuring equity in social health between members of stigmatized and dominant groups. It is our aim to point toward a framework for scholars to further push the boundaries in understanding the social consequences of stigma.

Background: The cellular mechanisms underlying progression from paroxysmal to persistent atrial fibrillation (AF) are not fully understood, but alterations in (late) sodium current (INa) have been proposed. Human studies investigating electrophysiological changes at the paroxysmal stage of AF are sparse, with the majority employing right atrial appendage cardiomyocytes (CMs). We here investigated action potential (AP) characteristics and (late) INa remodelling in left atrial appendage CMs (LAA-CMs) from patients with paroxysmal and persistent AF and patients in sinus rhythm (SR), as well as the potential contribution of the “neuronal” sodium channel SCN10A/NaV1.8. Methods: Peak INa, late INa and AP properties were investigated through patch-clamp analysis on single LAA-CMs, whereas quantitative polymerase chain reaction was used to assess SCN5A/SCN10A expression levels in LAA tissue. Results: In paroxysmal and persistent AF LAA-CMs, AP duration was shorter than in SR LAA-CMs. Compared with SR, peak INa and SCN5A expression were significantly decreased in paroxysmal AF, whereas they were restored to SR levels in persistent AF. Conversely, although late INa was unchanged in paroxysmal AF compared with SR, it was significantly increased in persistent AF. Peak or late Nav1.8-based INa was not detected in persistent AF LAA-CMs. Similarly, expression of SCN10A was not observed in LAAs at any stage. Conclusions: Our findings demonstrate differences in (late) INa remodeling in LAA-CMs from patients with paroxysmal vs persistent AF, indicating distinct cellular proarrhythmic mechanisms in different AF forms. These observations are of particular relevance when considering potential pharmacologic approaches targeting (late) INa in AF.

STUDY QUESTIONWhat are the long-term outcomes after allocation to use of gonadotrophins versus clomiphene citrate (CC) with or without IUI in women with normogonadotropic anovulation and clomiphene failure?SUMMARY ANSWERAbout four in five women with normogonadotropic anovulation and CC failure had a live birth, with no evidence of a difference in pregnancy outcomes between the allocated groups.WHAT IS KNOWN ALREADYCC has long been used as first line treatment for ovulation induction in women with normogonadotropic anovulation. Between 2009 and 2015, a two-by-two factorial multicentre randomized clinical trial in 666 women with normogonadotropic anovulation and six cycles of CC failure was performed (M-ovin trial). This study compared a switch to gonadotrophins with continued treatment with CC for another six cycles, with or without IUI within 8 months. Switching to gonadotrophins increased the chance of conception leading to live birth by 11% over continued treatment with CC after six failed ovulatory cycles, at a cost of €15 258 per additional live birth. The addition of IUI did not significantly increase live birth rates.STUDY DESIGN, SIZE, DURATIONIn order to investigate the long-term outcomes of switching to gonadotrophins versus continuing treatment with CC, and undergoing IUI versus continuing with intercourse, we conducted a follow-up study. The study population comprised all women who participated in the M-ovin trial.PARTICIPANTS/MATERIALS, SETTING, METHODSThe participating women were asked to complete a web-based questionnaire. The primary outcome of this study was cumulative live birth. Secondary outcomes included clinical pregnancies, multiple pregnancies, miscarriage, stillbirth, ectopic pregnancy, fertility treatments, neonatal outcomes and pregnancy complications.MAIN RESULTS AND THE ROLE OF CHANCEWe approached 564 women (85%), of whom 374 (66%) responded (184 allocated to gonadotrophins; 190 to CC). After a median follow-up time of 8 years, 154 women in the gonadotrophin group had a live birth (83.7%) versus 150 women in the CC group (78.9%) (relative risk (RR) 1.06, 95% CI 0.96–1.17). A second live birth occurred in 85 of 184 women (49.0%) in the gonadotrophin group and in 85 of 190 women (44.7%) in the CC group (RR 1.03, 95% CI 0.83–1.29). Women allocated to gonadotrophins had a third live birth in 6 of 184 women (3.3%) and women allocated to CC had a third live birth in 14 of 190 women (7.4%). There were respectively 12 and 11 twins in the gonadotrophin and CC groups. The use of fertility treatments in the follow-up period was comparable between both groups. In the IUI group, a first live birth occurred in 158 of 192 women (82.3%) and while in the intercourse group, 146 of 182 women (80.2%) reached at least one live birth (RR: 1.03 95% CI 0.93–1.13; 2.13%, 95% CI −5.95, 10.21).LIMITATIONS, REASONS FOR CAUTIONWe have complete follow-up results for 57% of the women.There were 185 women who did not respond to the questionnaire, while 102 women had not been approached due to missing contact details. Five women had not started the original trial.WIDER IMPLICATIONS OF THE FINDINGSWomen with normogonadotropic anovulation and CC failure have a high chance of reaching at least one live birth. In terms of pregnancy rates, the long-term differences between initially switching to gonadotrophins are small compared to continuing treatment with CC.STUDY FUNDING/COMPETING INTEREST(S)The original study received funding from the Dutch Organization for Health Research and Development (ZonMw number: 80-82310-97-12067). A.H. reports consultancy for development and implementation of a lifestyle App, MyFertiCoach, developed by Ferring Pharmaceutical Company. M.G. receives unrestricted grants for scientific research and education from Ferring, Merck and Guerbet. B.W.M. is supported by an NHMRC Investigatorgrant (GNT1176437). B.W.M. reports consultancy for ObsEva and Merck and travel support from Merck. All other authors have nothing to declare.TRIAL REGISTRATION NUMBERThis follow-up study was registered in the OSF Register, https://osf.io/pf24m. The original M-ovin trial was registered in the Netherlands Trial Register, number NTR1449.

BACKGROUND: Assisted reproductive technology (ART) has allowed couples with a family history of a monogenic genetic disease, or a disease-carrying gene, to reduce the chance of them having a child with the genetic disorder. This is achieved by genetically testing the embryos using an advanced process called preimplantation genetic testing for monogenic or single gene disorders (PGT-M), such as Huntington's disease or cystic fibrosis. This current terminology (PGT-M) has replaced the formerly-known preimplantation genetic diagnosis (PGD). During PGT-M, one or more embryo cells are biopsied and analysed for genetic or chromosomal anomalies before transferring the embryos to the endometrial cavity. Biopsy for PGT-M can be performed at day 3 of cleavage-stage embryo development when the embryo is at the six- to the eight-cell stage, with either one or two blastomeres being removed for analysis. Biopsy for PGT-M can also be performed on day 5 of the blastocyst stage of embryo development when the embryo has 80 to 100 cells, with five to six cells being removed for analysis. Day 5 biopsy has taken over from day 3 biopsy as the most widely-used biopsy technique; however, there is a lack of summarised evidence from randomised controlled trials (RCTs) that assesses the effectiveness and safety of day 5 biopsy compared to day 3 biopsy. Since biopsy is an invasive process, whether it is carried out at day 3 or day 5 of embryo development may have different impacts on further development, implantation, pregnancy, live birth and perinatal outcomes.OBJECTIVES: To assess the benefits and harms of day 5 embryo biopsy, in comparison to day 3 biopsy, in PGT-M in women undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles.SEARCH METHODS: We searched the following electronic bibliographic databases in December 2021 to identify relevant RCTs: the Cochrane Gynaecology and Fertility Group (CGFG) Specialised Trials Register; CENTRAL, MEDLINE, Embase and PsycINFO. We also handsearched grey literature, such as trial registers, relevant journals, reference lists, Google Scholar, and published conference abstracts.SELECTION CRITERIA: Eligible RCTs compared day 5 versus day 3 embryo biopsy for PGT-M. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcomes were live births and miscarriages. We calculated outcomes per woman/couple randomised and reported odds ratios (ORs) with 95% confidence intervals (CIs).MAIN RESULTS: We included one RCT involving 20 women. The evidence was of very low certainty; the main limitations of the study were serious risk of bias due to lack of blinding of study personnel, and imprecision. We are uncertain whether day 5 embryo biopsy compared to day 3 biopsy has an effect on live births (OR 1.50, 95% CI 0.26 to 8.82; 1 RCT, 20 women; very low-certainty evidence). The evidence suggests that if the chance of live birth following day 3 biopsy was assumed to be 40%, then the chance with day 5 biopsy is between 15% and 85%. It is also uncertain whether day 5 embryo biopsy compared to day 3 biopsy has an effect on miscarriages (OR 1.00, 95% CI 0.05 to 18.57; 1 RCT, 20 women; very low-certainty evidence). We are uncertain whether day 5 embryo biopsy compared to day 3 biopsy has an effect on other secondary outcome measures, including viable intrauterine pregnancies (OR 2.25, 95% CI 0.38 to 13.47; 1 RCT, 20 women; very low-certainty evidence), ectopic pregnancies (OR 0.16, 95% CI 0.01 to 3.85; 1 RCT, 20 women; very low-certainty evidence), stillbirths (OR not estimable as no events in either group; 1 RCT, 20 women; very low-certainty evidence) or termination of pregnancies (OR 3.32, 95% CI 0.12 to 91.60; 1 RCT, 20 women; very low-certainty evidence). No studies reported on gestational age at birth, birthweight, neonatal mortality and major congenital anomaly.AUTHORS' CONCLUSIONS: We are uncertain if there is a difference in live births and miscarriages, viable intrauterine pregnancies, ectopic pregnancies, stillbirths or termination of pregnancies between day 5 and day 3 embryo biopsy for PGT-M. There was insufficient evidence to draw any conclusions regarding other adverse outcomes. The results should be interpreted with caution, as the evidence was of very low certainty due to limited studies, high risk of bias in the included study, and an overall low level of precision.

Background: The safety and effectiveness of rivaroxaban versus vitamin K antagonists (standard of care [SOC]) for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) was evaluated in Europe. Research design and methods: Observational studies were conducted in the UK, the Netherlands, Germany, and Sweden. Primary safety outcomes were hospitalization for intracranial hemorrhage, gastrointestinal bleeding, or urogenital bleeding among new users of rivaroxaban and SOC with NVAF; outcomes were analyzed using cohort (rivaroxaban or SOC use) and nested case–control designs (current vs nonuse). Statistical analyses comparing rivaroxaban and SOC cohorts were not performed. Results: Overall, 162,919 rivaroxaban users and 177,758 SOC users were identified. In the cohort analysis, incidence ranges for rivaroxaban users were 0.25–0.63 events per 100 person-years for intracranial bleeding, 0.49–1.72 for gastrointestinal bleeding, and 0.27–0.54 for urogenital bleeding. Corresponding ranges for SOC users were 0.30–0.80, 0.30–1.42, and 0.24–0.42, respectively. In the nested case–control analysis, current SOC use generally presented a greater risk of bleeding outcomes than nonuse. Rivaroxaban use (vs nonuse) was associated with a higher risk of gastrointestinal bleeding, but a similar risk of intracranial or urogenital bleeding, in most countries. Ischemic stroke incidence ranged from 0.31 to 1.52 events per 100 person-years for rivaroxaban users. Conclusions: Incidences of intracranial bleeding were generally lower with rivaroxaban than with SOC, whereas incidences of gastrointestinal and urogenital bleeding were generally higher. The safety profile of rivaroxaban for NVAF in routine practice is consistent with findings from randomized controlled trials and other studies.

Background: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. Methods: Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (r g) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons). Results: ADHD and PTSD had consistent r g (r g range, 0.43–0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (β = 0.367; 95% CI, 0.186–0.552; p = 7.68 × 10 −5). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10 −4, p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98–3.53). Conclusions: Our findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.

Purpose: The purpose of this study was to gain a comprehensive understanding of participation situations that are challenging for people with communication problems, to provide input for the further development of potential items for the Communicative Participation Item Bank (CPIB). Method: A purposive sampling strategy was used to include a diverse group of people with communication problems. Diaries were used as a sensitizing exercise for inductive in-depth interviews. In these interviews, elements of communicative participation situations (concepts) were elicited that participants themselves experienced as difficult because of their communication problem. A thematic content analysis was used to identify overarching themes. In addition, new items were formulated based on the raw codes of the transcripts and linked to the International Classification of Functioning, Disability and Health Activity and Participation domains to examine the distribution of items across the breadth of the construct of communicative participation. Results: Eighteen interviews yielded 44 different concepts. They were clustered in six themes, which capture the person, location, topic, mode, moment, and pace of communication. In total, 103 new items measuring communicative participation were formulated. Most of these items relate to International Classification of Functioning, Disability and Health Activity and Participation domains “interpersonal interactions and relationships,” “major life areas,” and “community, social, and civic life.” Conclusions: This study resulted in an overview of self-reported barriers in daily communicative participation experienced by people with communication problems. These communicative participation situations can be captured within 44 concepts, which are covered by six themes. Future work should investigate if the newly written items can be added to the CPIB. The concepts and the themes can be used in designing and delivering a participation-focused intervention for this population.

The immunopathophysiological mechanisms underlying chronic inflammatory demyelinating polyneuropathy (CIDP) in an individual patient are largely unknown. Better understanding of these mechanisms may aid development of biomarkers and targeted therapies. Both B- and T-cell dominant mechanisms have been implicated. We therefore investigated whether B-cell and T-cell receptor (BCR/TCR) repertoires might function as immunological biomarkers in CIDP. In this prospective cohort study, we longitudinally sampled peripheral blood of CIDP patients in three different phases of CIDP: starting induction treatment (IT), starting withdrawal from IVIg maintenance treatment (MT), and patients in remission (R). BCR and TCR repertoires were analyzed using RNA based high throughput sequencing. In baseline samples, the number of total clones, the number of dominant BCR and TCR clones and their impact on the repertoire was similar for patients in the IT, MT, and remission groups compared with healthy controls. Baseline samples in the IT or MT did not predict treatment response or potential relapse at follow-up. Treatment responders in the IT group showed a potential IVIg-induced increase in the number of dominant BCR clones and their impact at follow-up (baseline1.0 [IQR 1.0-2.8] vs. 6 m 3.5 [0.3-6.8]; P

We assess Radder’s criticisms of the Netherlands Code of Conduct for Research Integrity and show that they either miss their mark or depend on controversial background assumptions about the purpose of the Code. Although Radder raises important questions about the broader roles and purposes of research in society, his conclusion that the Code should be revised in the ways he proposes is unjustified.

Background: In the Netherlands, lower high-risk human papillomavirus (hrHPV) positivity but higher cervical intraepithelial neoplasia (CIN) 2+ detection were found in self-collected compared with clinician-collected samples. To investigate the possible reason for these differences, we compared sociodemographic and screening characteristics of women and related these to screening outcomes. Methods: We extracted data from PALGA on all primary hrHPV screens and associated follow-up tests for 857,866 screened women, invited in 2017 and 2018. We linked these data with sociodemographic data from Statistics Netherlands. Logistic regression was performed for hrHPV positivity and CIN 2+/3+ detection. Results: Out of the 857,866 women, 6.8% chose to use a self-sampling device. A higher proportion of self-sampling users was ages 30 to 35 years, was not previously screened, was living in a one-person household, or was the breadwinner in the household. After adjustment for these factors self-sampling had lower hrHPV positivity (aOR, 0.65; 95% CI, 0.63–0.68)) as compared with clinician-collected sampling, as well as lower odds of CIN 2+ (aOR, 0.76; 95% CI, 0.70–0.82) and CIN 3+ (aOR, 0.86; 95% CI, 0.78–0.95) detection. Conclusions: It is likely that the observed differences between the two sampling methods are not only related to sociodemographic differences, but related to differences in screening test accuracy and/or background risk. Impact: Self-sampling can be used for targeting underscreened women, as a more convenient screening tool. Further investigation is required to evaluate how to implement self-sampling, when it is used as a primary instrument in routine screening. See related commentary by Arbyn et al., p. 159

Introduction: The corona virus (COVID-19) pandemic may have a prolonged impact on people's lives, with multiple waves of infections and lockdowns, but how a lockdown may alter emotional functioning is still hardly understood. Methods: In this 100-daily diaries study, we examined how to affect intensity and variability of adolescents (N = 159, Mage = 13.3, 61.6% female) and parents (N = 159, Mage = 45.3, 79.9% female) changed after the onset and during (>50 days) the second COVID-19 lockdown in the Netherlands, using preregistered piecewise growth models. Results: We found only an unexpected increase in parents' positive affect intensity after the lockdown onset, but no immediate changes in negative affect intensity or variability. However, both adolescents and parents reported gradual increases in negative affect intensity and variability as the lockdown prolonged. Lockdown effects did not differ between adolescents and parents. However, within groups, individuals differed. The individual differences in the effects were partly explained by life satisfaction, depressive symptoms, and self-reported lockdown impact. Conclusions: Overall, these findings suggests that a lockdown triggers changes in daily affective well-being especially as the lockdown prolongs. Individual differences in the effects indicate heterogeneity in the impact of the lockdown on daily affect that was partly explained by baseline life satisfaction and depressive symptoms. However, more knowledge on the causes of this heterogeneity is needed to be able to increase resilience to lockdown effects in the population.

The Barker Hypothesis posits that adverse intrauterine environments result in fetal growth restriction and increased risk of cardiometabolic disease through developmental compensations. Here we introduce a new statistical model using the genomic SEM software that is capable of simultaneously partitioning the genetic covariation between birthweight and cardiometabolic traits into maternally mediated and offspring mediated contributions. We model the covariance between birthweight and later life outcomes, such as blood pressure, non-fasting glucose, blood lipids and body mass index in the Norwegian HUNT study, consisting of 15,261 mother-eldest offspring pairs with genetic and phenotypic data. Application of this model showed some evidence for maternally mediated effects of systolic blood pressure on offspring birthweight, and pleiotropy between birthweight and non-fasting glucose mediated through the offspring genome. This underscores the importance of genetic links between birthweight and cardiometabolic phenotypes and offer alternative explanations to environmentally based hypotheses for the phenotypic correlation between these variables.

Background: Conflicting findings have described the association between prolonged heart rate-corrected QT interval (QTc) and cardiovascular disease. Aims: To identify articles investigating the association between QTc and cardiovascular disease morbidity and mortality, and to summarize the available evidence for the general and type 2 diabetes populations. Methods: A systematic search was performed in PubMed and Embase in May 2022 to identify studies that investigated the association between QTc prolongation and cardiovascular disease in both the general and type 2 diabetes populations. Screening, full-text assessment, data extraction and risk of bias assessment were performed independently by two reviewers. Effect estimates were pooled across studies using random-effect models. Results: Of the 59 studies included, 36 qualified for meta-analysis. Meta-analysis of the general population studies showed a significant association for: overall cardiovascular disease (fatal and non-fatal) (hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.33–2.12; I2 = 69%); coronary heart disease (fatal and non-fatal) in women (HR 1.27, 95% CI 1.08–1.50; I2 = 38%; coronary heart disease (fatal and non-fatal) in men (HR 2.07, 95% CI 1.26–3.39; I2 = 78%); stroke (HR 1.59, 95% CI 1.29–1.96; I2 = 45%); sudden cardiac death (HR 1.60, 95% CI 1.14–2.25; I2 = 68%); and atrial fibrillation (HR 1.55, 95% CI 1.31–1.83; I2 = 0.0%). No significant association was found for cardiovascular disease in the type 2 diabetes population. Conclusion: QTc prolongation was associated with risk of cardiovascular disease in the general population, but not in the type 2 diabetes population.

Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Objective: To assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease. Background: Migraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition. Methods: Linkage disequilibrium score regression and two-sample bidirectional Mendelian randomization analyses were performed using summary statistics from cohort-based genome-wide association studies of migraine (59,674 cases; 316,078 controls), IBD (25,042 cases; 34,915 controls) and celiac disease (11,812 or 4533 cases; 11,837 or 10,750 controls). Migraine with and without aura were analyzed separately, as were the two IBD subtypes Crohn's disease and ulcerative colitis. Positive control analyses and conventional Mendelian randomization sensitivity analyses were performed. Results: Migraine was not genetically correlated with IBD or celiac disease. No evidence was observed for IBD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.99-1.02, p = 0.703) or celiac disease (OR 1.00, 95% CI 0.99-1.02, p = 0.912) causing migraine or migraine causing either IBD (OR 1.08, 95% CI 0.96-1.22, p = 0.181) or celiac disease (OR 1.08, 95% CI 0.79-1.48, p = 0.614) when all participants with migraine were analyzed jointly. There was some indication of a causal association between celiac disease and migraine with aura (OR 1.04, 95% CI 1.00-1.08, p = 0.045), between celiac disease and migraine without aura (OR 0.95, 95% CI 0.92-0.99, p = 0.006), as well as between migraine without aura and ulcerative colitis (OR 1.15, 95% CI 1.02-1.29, p = 0.025). However, the results were not significant after multiple testing correction. Conclusions: We found no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease, although we obtained some indications of causal associations with migraine subtypes. Keywords: Mendelian randomization; celiac disease; gastrointestinal disease; genetic correlation; inflammatory bowel disease; migraine.

We investigated whether the outcome prediction of patients with aggressive B-cell lymphoma can be improved by combining clinical, molecular genotype, and radiomics features. MYC, BCL2, and BCL6 rearrangements were assessed using fluorescence in situ hybridization. Seventeen radiomics features were extracted from the baseline positron emission tomography–computed tomography of 323 patients, which included maximum standardized uptake value (SUVmax), SUVpeak, SUVmean, metabolic tumor volume (MTV), total lesion glycolysis, and 12 dissemination features pertaining to distance, differences in uptake and volume between lesions, respectively. Logistic regression with backward feature selection was used to predict progression after 2 years. The predictive value of (1) International Prognostic Index (IPI); (2) IPI plus MYC; (3) IPI, MYC, and MTV; (4) radiomics; and (5) MYC plus radiomics models were tested using the cross-validated area under the curve (CV-AUC) and positive predictive values (PPVs). IPI yielded a CV-AUC of 0.65 ± 0.07 with a PPV of 29.6%. The IPI plus MYC model yielded a CV-AUC of 0.68 ± 0.08. IPI, MYC, and MTV yielded a CV-AUC of 0.74 ± 0.08. The highest model performance of the radiomics model was observed for MTV combined with the maximum distance between the largest lesion and another lesion, the maximum difference in SUVpeak between 2 lesions, and the sum of distances between all lesions, yielding an improved CV-AUC of 0.77 ± 0.07. The same radiomics features were retained when adding MYC (CV-AUC, 0.77 ± 0.07). PPV was highest for the MYC plus radiomics model (50.0%) and increased by 20% compared with the IPI (29.6%). Adding radiomics features improved model performance and PPV and can, therefore, aid in identifying poor prognosis patients.

T-cell dysregulation in chronic lymphocytic leukemia (CLL) associates with low response rates to autologous T cell-based therapies. How CLL affects antigen-specific T-cell responses remains largely unknown. We investigated (epi)genetic and functional consequences of antigen-specific T-cell responses in presence of CLL in vitro and in an adoptive-transfer murine model. Already at steady-state, antigen-experienced patient-derived T cells were skewed towards short-lived effector cells (SLEC) at the expense of memory-precursor effector cells (MPEC). Stimulation of these T cells in vitro showed rapid induction of effector genes and suppression of key memory transcription factors only in presence of CLL cells, indicating epigenetic regulation. This was investigated in vivo by following antigen-specific responses of naive OT-I CD8(+) cells to mCMV-OVA in presence/absence of TCL1 B-cell leukemia. Presence of leukemia resulted in increased SLEC formation, with disturbed inflammatory cytokine production. Chromatin and transcriptome profiling revealed strong epigenetic modifications, leading to activation of an effector and silencing of a memory profile through presence of CLL cells. Secondary challenge in vivo confirmed dysfunctional memory responses by antigen-experienced OT-I cells generated in presence of CLL. Altogether, we show that presence of CLL induces a short-lived effector phenotype and impaired memory responses by epigenetic reprogramming during primary responses.

Background and aims: Cerebrotendinous Xanthomatosis (CTX) is a treatable disorder of bile acid synthesis caused by deficiency of 27-sterol hydroxylase -encoded by CYP27A1- leading to gastrointestinal and progressive neuropsychiatric symptoms. Biochemically, CTX is characterized by accumulation of the bile alcohol cholestanetetrol glucuronide (GlcA-tetrol) and the deficiency of tauro-chenodeoxycholic acid (t-CDCA) and tauro-trihydroxycholestanoic acid (t-THCA). Materials and Methods: To ascertain the feasibility of CTX newborn screening (NBS) we performed a study with deidentified Dutch dried blood spots using reagents and equipment that is frequently used in NBS laboratories. 20,076 deidentified newborn blood spots were subjected to flow-injection (FIA)-MS/MS and UPLC-MS/MS analysis to determine the concentration of GlcA-tetrol and calculate the GlcA-tetrol/t-CDCA and t-THCA/GlcA-tetrol ratios. Results: Using UPLC-MS/MS analysis both GlcA-tetrol concentration and/or metabolite ratios GlcA-tetrol/t-CDCA proved to be informative biomarkers; newborn DBS results did not overlap with those of the CTX patients. For FIA-MS/MS, GlcA-tetrol also was an excellent marker but when using the combination of the GlcA-tetrol/t-CDCA and t-THCA/GlcA-tetrol ratios also did not yield any screen positives. Conclusion: Newborn screening for CTX using only metabolite ratios following the measurement of three CTX biomarkers is possible using either FIA-MS/MS or UPLC-MS/MS, which paves the way for introduction of CTX NBS.

Background: Problematic sleep in infants can have a high impact on families. We examined parental discontent with infant sleep in the first six months of life and parent-perceived problematic sleep during the second year of life. Methods: We used Sarphati Cohort data of 1471 children. During periodic youth health care visits in the first six months of life, professionals registered parental discontent with infant sleep. In the second year of life, parents filled out the Brief Infant Sleep Questionnaire (BISQ), from which we defined parent-perceived problematic sleep and BISQ-defined problematic sleep. We examined the association of parental discontent with infant sleep during the first six months with both BISQ-derived outcomes up to age two, using multivariable logistic regression analysis. Results: 26% of parents were discontented with infant sleep during the first six months of life. During the second year of life, 27% of the parents perceived their child’s sleep as problematic, and 9% of the infants had BISQ-defined problematic sleep. Early parental discontent with infant sleep was associated with parent-perceived problematic sleep [adjusted OR 2.50 (95% CI 1.91–3.28)], and BISQ-defined problematic sleep [adjusted OR 1.88 (1.11–3.17)]. Conclusions: Early registered parental discontent with infant sleep was a predictor of parent-perceived problematic sleep in early toddlerhood. Registering parental discontent during infancy might enable professionals to identify a group of infants at risk for later problematic sleep. We recommend screening and parental support for sleep difficulties in an early stage.

Little is known about the safety and surgical outcomes of mastectomy after breast reduction in the trans male population. Several concerns have been voiced that performing mastectomy with prior breast reduction surgery, increases the risk for complications and revision surgery. All transgender men with a history of breast reduction, who underwent a mastectomy at our center between 01-1990 and 01-2021 were identified from our hospital registry. A retrospective chart study was conducted recording surgical characteristics, surgical complications, revision surgery, and clinical follow-up. A total of 1362 subcutaneous mastectomies were performed between 01-1990 and 01-2021. A total of 36 (2.6%) individuals were included (35 bilateral and 1 unilateral breast reduction). The mean age at mastectomy was 37 ? 10 years, and the median time between breast reduction and mastectomy was 6.3 years (range 1.0?31.1). Most individuals underwent a Wise-pattern breast reduction (91%) and a double incision mastectomy with free nipple grafts (86%). Following mastectomy, one acute reoperation was performed because of hemorrhage (3%). Partial pedicled nipple necrosis was seen in 7% and (partial) non-take of nipple grafts in 4%. Scar revisions were performed in 9%, dogear corrections in 20%, and both nipple corrections, and contour corrections in 6%. When comparing the outcomes in literature for surgical complications, scar revision, contour correction or nipple areolar complex revision, no clear disadvantage seems to be present when performing mastectomy after breast reduction. Mastectomy is a safe procedure in transgender men with a history of breast reduction.

Contains fulltext : 291201.pdf (Publisher’s version ) (Open Access) OBJECTIVES: To investigate the role of specialised genitourinary multidisciplinary team meetings (MDTMs) in decision-making and identify factors that influence the probability of receiving a treatment plan with curative intent for patients with muscle invasive bladder cancer (MIBC). PATIENTS AND METHODS: Data relating to patients with cT2-4aN0/X-1 M0 urothelial cell carcinoma, diagnosed between November 2017 and October 2019, were selected from the nationwide, population-based Netherlands Cancer Registry ('BlaZIB study'). Curative treatment options were defined as radical cystectomy (RC) with or without neoadjuvant chemotherapy, chemoradiation or brachytherapy. Multilevel logistic regression analyses were used to examine the association between MDTM factors and curative treatment advice and how this advice was followed. RESULTS: Of the 2321 patients, 2048 (88.2%) were discussed in a genitourinary MDTM. Advanced age (>80 years) and poorer World Health Organization performance status (score 1-2 vs 0) were associated with no discussion (P

Purpose To relate [18F]fluoride uptake on PET with abnormalities on magnetic resonance imaging (MRI) and conventional radiography (CR) in ankylosing spondylitis (AS) patients. Methods Ten clinically active AS patients (female 6/10, age 38 ± 11 years) were included, and both spine and SI-joints were examined. PET scans were dichotomously scored for enhanced [18F]fluoride uptake, MRI scans were scored for fatty lesions, erosions, ankylosis, and bone marrow edema (BME), and CR was scored for erosions, syndesmophytes, and ankylosis. The overlap of lesions across all modalities was evaluated through univariate and multivariate analyses using a generalized mixed model. Results In the spine, 69 lesions with enhanced [18F]fluoride uptake, 257 MRI lesions, and 88 CR lesions were observed. PET lesions were mostly located in costovertebral and facet joints, outside the field of view (FOV) of the MRI and CR. However, PET lesions inside the FOV of MRI and CR partially showed no abnormality on MRI and CR. In lesions with abnormalities on multiple modalities, both univariate and multivariate analysis showed that PET activity had the strongest association with BME on MRI and ankylosis on CR. In the SI joints, 15 lesions (75%) with PET uptake were found, with 87% showing abnormalities on MRI and CR. Conclusion [18F]fluoride PET lesions are often found outside the scope of MRI and CR, and even in the same location show only partial overlap with abnormalities on MRI (especially BME) and CR (especially ankylosis). This suggests that [18F]fluoride PET partially visualizes aspects of AS separate from MRI and CR, providing novel information. Clinical trial registration NL43223.029.13 registered at 02-05-2013. https://www.toetsingonline.nl/to/ccmo_search.nsf/fABRpop?readform&unids=C1257BA2002CC066C1257B4E0049A65A

Background Digital interventions for anxiety disorders are a promising solution to address barriers to evidence-based treatment access. Precise and powerful estimates of digital intervention effectiveness for anxiety disorders are necessary for further adoption in practice. The present systematic review and meta-analysis examined the effectiveness of digital interventions across all anxiety disorders and specific to each disorder v. wait-list and care-as-usual controls. Methods A systematic search of bibliographic databases identified 15 030 abstracts from inception to 1 January 2020. Forty-seven randomized controlled trials (53 comparisons; 4958 participants) contributed to the meta-analysis. Subgroup analyses were conducted by an anxiety disorder, risk of bias, treatment support, recruitment, location and treatment adherence. Results A large, pooled effect size of g = 0.80 [95% Confidence Interval: 0.68–0.93] was found in favor of digital interventions. Moderate to large pooled effect sizes favoring digital interventions were found for generalized anxiety disorder (g = 0.62), mixed anxiety samples (g = 0.68), panic disorder with or without agoraphobia (g = 1.08) and social anxiety disorder (g = 0.76) subgroups. No subgroups were significantly different or related to the pooled effect size. Notably, the effects of guided interventions (g = 0.84) and unguided interventions (g = 0.64) were not significantly different. Supplemental analysis comparing digital and face-to-face interventions (9 comparisons; 683 participants) found no significant difference in effect [g = 0.14 favoring digital interventions; Confidence Interval: −0.01 to 0.30]. Conclusion The precise and powerful estimates found further justify the application of digital interventions for anxiety disorders in place of wait-list or usual care.

Introduction Although visual and quantitative assessments of [18F]FDG PET/CT studies typically rely on liver uptake value as a reference or normalisation factor, consensus or consistency in measuring [18F]FDG uptake is lacking. Therefore, we evaluate the variation of several liver standardised uptake value (SUV) measurements in lymphoma [18F]FDG PET/CT studies using different uptake metrics. Methods PET/CT scans from 34 lymphoma patients were used to calculate SUVmaxliver, SUVpeakliver and SUVmeanliver as a function of (1) volume-of-interest (VOI) size, (2) location, (3) imaging time point and (4) as a function of total metabolic tumour volume (MTV). The impact of reconstruction protocol on liver uptake is studied on 15 baseline lymphoma patient scans. The effect of noise on liver SUV was assessed using full and 25% count images of 15 lymphoma scans. Results Generally, SUVmaxliver and SUVpeakliver were 38% and 16% higher compared to SUVmeanliver. SUVmaxliver and SUVpeakliver increased up to 31% and 15% with VOI size while SUVmeanliver remained unchanged with the lowest variability for the largest VOI size. Liver uptake metrics were not affected by VOI location. Compared to baseline, liver uptake metrics were 15–18% and 9–18% higher at interim and EoT PET, respectively. SUVliver decreased with larger total MTVs. SUVmaxliver and SUVpeakliver were affected by reconstruction protocol up to 62%. SUVmax and SUVpeak moved 22% and 11% upward between full and 25% count images. Conclusion SUVmeanliver was most robust against VOI size, location, reconstruction protocol and image noise level, and is thus the most reproducible metric for liver uptake. The commonly recommended 3 cm diameter spherical VOI-based SUVmeanliver values were only slightly more variable than those seen with larger VOI sizes and are sufficient for SUVmeanliver measurements in future studies. Trial registration EudraCT: 2006–005,174-42, 01–08-2008.

Introduction: This population-based cohort study analysed treatment, overall survival (OS), and independent prognostic factors for OS in gastric cancer patients with liver metastases. Methods: Between 2015 and 2017, patients with synchronous metastatic gastric or gastroesophageal junction adenocarcinoma limited to the liver were included from the prospectively maintained population-based Netherlands Cancer Registry. Liver oligometastatic disease (OMD) was defined as ≤3 liver metastases. The primary outcome was OS. Independent prognostic factors for OS were analysed using multivariable Cox regression analysis. Results: A total 295 patients with metastases limited to the liver were included. The primary tumour was resected in four patients (1.4%). Treatment for liver metastases consisted of chemotherapy alone (28.1%), trastuzumab plus chemotherapy (4.7%), surgery (1.0%), or best supportive care (67.5%). Median OS across all included patients was 4.0 months (95% confidence interval [CI]: 3.1–4.5). Liver OMD was detected in 77 patients (26%). Treatment for liver OMD consisted of chemotherapy alone (24.6%), trastuzumab plus chemotherapy (5.2%), surgery (3.9%), or best supportive care (67.5%). Median OS among patients with liver OMD was 5.7 months (95% CI: 4.8–7.5). Across all patients, better OS was independently associated with liver OMD (hazard ratio [HR] 0.66, 95% CI: 0.50–0.87), trastuzumab (HR 0.41, 95% CI: 0.23–0.72) but not with triplet compared with doublet chemotherapy (HR 0.94, 95% CI: 0.57–2.87). Worse OS was independently associated with unknown nodal stage versus cN0 (HR 1.74, 95% CI: 1.17–2.60), diffuse-type versus intestinal-type adenocarcinoma (HR 2.06, 95% CI: 1.32–3.20), and monotherapy or best supportive care versus doublet chemotherapy (HR 1.72, 95% CI: 1.03–2.87, and HR 3.61, 95% CI: 2.55–5.10, respectively). Conclusion: In this population-based cohort study, liver OMD was detected in 26% of patients. Liver OMD and trastuzumab treatment were independently associated with better OS while triplet as compared with doublet chemotherapy was not. OS among patients with liver OMD nevertheless remained poor. The concept of OMD and the benefit of resection of liver OMD may still have been relatively unknown in this disease type during the study inclusion years.

BACKGROUND: Single nucleotide polymorphism-based heritability is a fundamental quantity in the genetic analysis of complex traits. For case-control phenotypes, for which the continuous distribution of risk in the population is unobserved, observed-scale heritability estimates must be transformed to the more interpretable liability scale. This article describes how the field standard approach incorrectly performs the liability correction in that it does not appropriately account for variation in the proportion of cases across the cohorts comprising the meta-analysis. We propose a simple solution that incorporates cohort-specific ascertainment using the summation of effective sample sizes across cohorts. This solution is applied at the stage of single nucleotide polymorphism-based heritability estimation and does not require generating updated meta-analytic genome-wide association study summary statistics.METHODS: We began by performing a series of simulations to examine the ability of the standard approach and our proposed approach to recapture liability-scale heritability in the population. We went on to examine the differences in estimates obtained from these 2 approaches for real data for 12 major case-control genome-wide association studies of psychiatric and neurologic traits.RESULTS: We found that the field standard approach for performing the liability conversion can downwardly bias estimates by as much as approximately 50% in simulation and approximately 30% in real data.CONCLUSIONS: Prior estimates of liability-scale heritability for genome-wide association study meta-analysis may be drastically underestimated. To this end, we strongly recommend using our proposed approach of using the sum of effective sample sizes across contributing cohorts to obtain unbiased estimates.

Contains fulltext : 290851.pdf (Publisher’s version ) (Open Access) BACKGROUND AND OBJECTIVES: Our objective was to develop an extension of the widely used GIN-McMaster Guideline Development Checklist and Tool for the integration of quality assurance and improvement (QAI) schemes with guideline development. METHODS: We used a mixed-methods approach incorporating evidence from a systematic review, an expert workshop and a survey of experts to iteratively create an extension of the checklist for QAI through three rounds of feedback. As a part of this process, we also refined criteria of a good guideline-based quality indicator. RESULTS: We developed a 40-item checklist extension addressing steps for the integration of QAI into guideline development across the existing 18 topics and created one new topic specific to QAI. The steps span from 'organization, budget, planning and training', to updating of QAI and guideline implementation. CONCLUSION: The tool supports integration of QAI schemes with guideline development initiatives and it will be used in the forthcoming integrated European Commission Initiative on Colorectal Cancer. Future work should evaluate this extension and QAI items requiring additional support for guideline developers and links to QAI schemes. 01 februari 2023

Contains fulltext : 290804.pdf (Publisher’s version ) (Closed access) Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention. 01 februari 2023

Contains fulltext : 291299.pdf (Publisher’s version ) (Open Access) With the trend towards childhood surgery in patients with Ebstein anomaly (EA), thorough imaging is crucial for patient selection. This study aimed to assess biventricular function by echocardiography and cardiac magnetic resonance (CMR) and compare EA severity classifications. Twenty-three patients (8-17 years) underwent echocardiography and CMR. Echocardiographic parameters included tricuspid annular plane systolic excursions (TAPSE), fractional area change of the functional right ventricle (fRV-FAC), fRV free wall peak systolic myocardial velocity (fRVs'), and tricuspid regurgitation (TR). End-diastolic and end-systolic volume (EDV resp. ESV), fRV- and LV ejection fraction (EF) and TR were obtained by CMR. EA severity classifications included displacement index, Celermajer index and the total-right/left-volume index. Median fRV-FAC was 38% (IQR 33-42). TAPSE and fRVs' were reduced in 39% and 75% of the patients, respectively. Echocardiographic TR was visually graded as mild, moderate, or severe in nine, six and eight patients, respectively. By CMR, median fRVEF was 49% (IQR 36-58) and TR was graded as mild, moderate, or severe in nine, twelve and two patients, respectively. In 70% of cases, fRV-EDV was higher than LV-EDV. LVEF was decreased in 17 cases (74%). There was excellent correlation between echocardiography-derived fRV-FAC and CMR-derived fRVEF (rho = 0.812, p

Three families suspected of distal hereditary motor neuropathy underwent genetic screening with the aim to identify the molecular defect underlying the disease. The description of the identification reflects the shift in molecular diagnostics that was made during the last decades. Our candidate gene approach yielded a known pathogenic variant in BSCL2 (p.Asn88Ser) in one family, and via a CMT-capture, in HSPB1 (p.Arg127Trp), in addition to five other variations in Charcot-Marie-Tooth-related genes in the proband of the second family. In the third family, using whole exome sequencing, followed by linkage-by-location, a three base pair deletion in exon 33 of MYH7 (p.Glu1508del) was found, a reported pathogenic allele albeit for a myopathy. After identification of the causative molecular defect, cardiac examination was performed for patients of the third family and this demonstrated abnormalities in three out of five affected family members. Heterogeneity and expansion of clinical phenotypes beyond known characteristics requires a wider set of genes to be screened. Whole exome/genome analysis with limited prior clinical information may therefore be used to precede a detailed clinical evaluation in cases of large families, preventing screening of a too narrow set of genes, and enabling the identification of novel disease-associated genes. In our cases, the variants had been reported, and co-segregation analysis confirmed the molecular diagnosis.

Objectives: To evaluate the access to comprehensive diagnostics and novel antituberculosis medicines in European countries.Methods: We investigated the access to genotypic and phenotypic Mycobacterium tuberculosis drug susceptibility testing and the availability of antituberculosis drugs and calculated the cost of drugs and treatment regimens at major tuberculosis treatment centres in countries of the WHO European region where rates of drug-resistant tuberculosis are the highest among all WHO regions. Results were stratified by middle-income and high-income countries.Results: Overall, 43 treatment centres from 43 countries participated in the study. For WHO group A drugs, the frequency of countries with the availability of phenotypic drug susceptibility testing was as follows: (a) 75% (30/40) for levofloxacin, (b) 82% (33/40) for moxifloxacin, (c) 48% (19/40) for bedaquiline, and (d) 72% (29/40) for linezolid. Overall, of the 43 countries, 36 (84%) and 24 (56%) countries had access to bedaquiline and delamanid, respectively, whereas only 6 (14%) countries had access to rifapentine. The treatment of patients with extensively drug-resistant tuberculosis with a regimen including a carbapenem was available only in 17 (40%) of the 43 countries. The median cost of regimens for drug-susceptible tuberculosis, multidrug-resistant/rifampicin-resistant tuberculosis (shorter regimen, including bedaquiline for 6 months), and extensively drug-resistant tuberculosis (including bedaquiline, delamanid, and a carbapenem) were €44 (minimum–maximum, €15–152), €764 (minimum–maximum, €542–15152), and €8709 (minimum–maximum, €7965–11759) in middle-income countries (n = 12) and €280 (minimum–maximum, €78–1084), €29765 (minimum–maximum, €11116–40584), and €217591 (minimum–maximum, €82827–320146) in high-income countries (n = 29), respectively.Discussion: In countries of the WHO European region, there is a widespread lack of drug susceptibility testing capacity to new and repurposed antituberculosis drugs, lack of access to essential medications in several countries, and a high cost for the treatment of drug-resistant tuberculosis.